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Modern anticancer therapies aim to attack tumor cells while sparing healthy tissue. An interdisciplinary team of researchers at Helmholtz-Zentrum Dresden-Rossendorf (HZDR) and FU Berlin has made important progress in this area: the scientists have produced tiny nanoparticles that are designed to specifically target cancer cells. They can navigate directly to the tumor cells and visualize those using advanced imaging techniques. Both in petri dishes and animal models, the scientists were able to effectively guide the nanoparticles to the cancer cells. The next step is to combine the new technique with therapeutic approaches.

The HZDR researchers start out with tiny, biocompatible nanoparticles made of so-called dendritic polyglycerols that serve as carrier molecules.

We can modify these particles and introduce various functions. For example, we can attach an antibody fragment to the particle that specifically binds to cancer cells. This antibody fragment is our targeting moiety that directs the nanoparticle to the tumor."

Dr. Kristof Zarschler, research associate at HZDR's Institute of Radiopharmaceutical Cancer Research

The target of the modified nanoparticles is an antigen known as EGFR (epidermal growth factor receptor). In certain types of cancer, such as breast cancer or head and neck tumors, this protein is overexpressed on the surface of the cells. "We were able to show that our designed nanoparticles preferentially interact with the cancer cells via these receptors," confirms Dr. Holger Stephan, leader of the Nanoscalic Systems Group at HZDR. "In control tests with similar nanoparticles that had been modified with an unspecific antibody, significantly fewer nanoparticles accumulated at the tumor cells."

The scientists intensively studied the nanoparticles' behavior both in cell cultures and in an animal model. For this purpose, they provided the nanoparticles with additional reporter characteristics, as Kristof Zarschler explains: "We used two complementary possibilities. In addition to the antibodies, we attached dye molecules and radionuclides to the nanoparticles. The dye molecule emits in the near infrared spectrum that penetrates the tissue and can be visualized with an appropriate microscope. The dye thus reveals where exactly the nanoparticles are located." The radionuclide, copper-64, fulfils a similar purpose. It emits radiation that is detected by a PET scanner (positron emission tomography). The signals can then be converted into a three-dimensional image that visualizes the distribution of the nanoparticles in the organism.

Excellent properties in living organisms

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Using these imaging techniques, researchers have been able to show that nanoparticle accumulation in the tumor tissue reaches maximum two days after administration to mice. The labelled nanoparticles are subsequently eliminated via the kidneys without being a burden for the body. "They are apparently ideal in size and properties," says Holger Stephan. "Smaller particles are filtered out of the blood in just a few hours and thus only have a short-term impact. If, on the other hand, the particles are too big, they accumulate in the spleen, liver or lungs and cannot be removed from the body via the kidneys and bladder." The interplay between the nanoparticles with an exact size of three nanometers and the attached antibody fragments evidently has a positive influence on the distribution and retention of the antibody in the organism as well as on its excretion profile.

In future experiments, the HZDR researchers want to test whether they can modify their system to carry other components. Kristof Zarschler describes the plans: "You can take these nanoparticles and functionalize them with an active substance. Then you can deliver a drug directly to the tumor. This might be a therapeutic radionuclide that destroys the tumor cells." It is also possible to attach antibody fragments specific for proteins other than EGFR to target different types of cancer.

Source:

Helmholtz-Zentrum Dresden-Rossendorf

Journal reference:

Pant, K., et al. (2019) Active targeting of dendritic polyglycerols for diagnostic cancer imaging. Small. doi.org/10.1002/smll.201905013.

A new simple blood test for brain tumors that could be used by GPs in primary care is being developed thanks to funding of nearly £500,000 by Cancer Research UK. Around 60,000 patients in the UK are living with a brain tumor but only 20 per cent of patients are still alive five years after diagnosis, partly because they present late with large inoperable tumors.

The University of Bristol-led research project to develop an affordable, point of care blood test to diagnose brain tumors earlier using fluorescent carbon dots and nanophotonics will be headed by Dr. Kathreena Kurian, Associate Professor in Brain Tumour Research and Dr. Sabine Hauert, Senior Lecturer in Robotics in collaboration with co-investigators: Professors Carmen Galan and Richard Martin at the University of Bristol; Dr. Neciah Dorh at FluoretiQ Limited and Dr. Helen Bulbeck at Brainstrust.

The cross-disciplinary research project brings together medical practitioners, along with experts in population health, nanoparticle engineering and detection, as well as computational modeling.

Dr. Kathreena Kurian, Head of the Brain Tumour Research Centre at the University of Bristol, said:

A simple blood test carried out by GPs would help decision-making and early diagnosis. This would revolutionize care by speeding up diagnosis, reducing costs to the NHS, anxiety of unnecessary scans and reducing the number of patients presenting with inoperable large brain tumors.

Additionally, this test could be used as an early monitor of brain tumor recurrence. Our work will be followed by a multicentre cohort biomarker study to determine the effectiveness of the test in a real-world setting."

Dr. Sabine Hauert from the Department of Engineering Mathematics and Bristol Robotics Laboratory (BRL), added: "Nanoparticles have shown promise in early detection of cancer by fluorescent labeling of very low levels of biomarkers in blood samples and other fluids."

Dr. Alexis Webb, Cancer Research UK's senior early detection funding manager, said:

At the moment the number of people who survive after a brain tumor diagnosis remains low and little has changed in over a generation. We're proud to support this innovative project and funding brain tumor research remains a priority for the charity. We need better techniques to diagnose brain tumors earlier, when more treatment options are available, to secure a future for more people affected by the disease."

Professor Carmen Galan, Professor of Organic and Biological Chemistry in the School of Chemistry, who has developed the fluorescent carbon-based nanomaterials that form the basis for the project, explained: "The fluorescent nanoprobes are produced by low-cost renewable routes and we have shown that we can decorate them with different biomolecules to target specific biomarkers in physiological conditions, which is really exciting."

Dr. Neciah Dorh, CEO of FluoretiQ Limited, stated:

As a diagnostics company, we are passionate about creating technology that can improve people's lives and we see this project as natural extension of the work that we are currently doing in infectious disease."

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In the UK in 2013, 38 percent of brain tumor patients visited their GP five times or more before being referred for diagnosis by imaging MRI/CT scan and neurosurgical biopsy, because the symptoms such as headache are non-specific, so there is an urgent need to develop new tests for brain tumors to help GPs diagnose brain tumors earlier.

There is a pressing need for the discovery of new blood biomarkers for brain cancer and state-of-the-art technology that allows for its sensitive detection. The aims of the research project are:

  • discover novel biomarkers, in addition to known markers such as Glial fibrillary acidic protein (GFAP), which will be used as a baseline;
  • implement a computational model to predict biomarker levels in blood;
  • develop a fluorescent nanoparticle that can label this marker in blood;
  • work with Bristol-based start-up FluoretiQ towards an affordable near patient testing solution.

Glioblastoma is the most common type of malignant brain tumor among adults and it is usually very aggressive, which means it can grow fast and spread quickly. It is characterized by abnormal blood vessels following a leaky blood-brain barrier (BBB). GFAP is unique to the brain and not present in blood that circulates throughout the body. Antibodies in GFAP are used to diagnose gliomas in tissue samples. There is evidence that GFAP crosses the leaky BBB and is an early non-specific peripheral blood biomarker which predates the clinical diagnosis of glioblastoma.

However, GFAP levels are too low for routine detection by routine protein detection tests such as ELISA. The research team has already identified other novel potential protein biomarkers of brain tumours using the epidemiological method, Mendelian Randomization, which may be present in low levels in the blood.

Fluorescent carbon dots (FCDs), also known as nanoparticles, are cheap and easy to create using a three-minute synthesis. FCDs can be readily attached to ligands such as antibodies targeting specific protein markers. FCDs labeling biomarkers can then be detected using nanophotonic technology, which has been developed by FluoretiQ, for rapid, sensitive, and low-cost diagnosis. Computational modeling will then be used to predict tumor size given biomarker availability in blood and establish the theoretical limits of the detection.

Source:

University of Bristol